Diets rich in fruits and vegetables are associated with decreased risk of cardiovascular disease and cancer. Biomarkers of oxidative DNA damage and lipid peroxidation can be used to establish the role of antioxidants in this protection and the optimal intake of those antioxidants. This concept is based on the presumptions that oxidative DNA damage is a significant contributor to the age-related development of some cancers and that lipid peroxidation plays a key role in the development of cardiovascular disease. Mass spectrometric measurements of various families of isoprostanes (F2-, F3-, and F4-isoprostanes) and of multiple DNA base oxidation products are probably the most promising biomarkers for use in human nutritional intervention studies. Biomarker studies should precede, as well as accompany, major intervention trials that measure disease incidence. The use of biomarkers provides a logical scientific basis for major intervention trials of antioxidants; such trials will, in turn, eventually validate or disprove the biomarker concept.